Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.

The spread of activation in semantic networks can be measured using semantic and indirect semantic priming effects in lexical decision tasks (Spitzer et al 1993a and b). For example, in thought-disordered schizophrenic patients, activation spreads faster and farther than in non-thought-disordered patients and normal subjects, which results in an increased direct and indirect semantic priming effect (see below). This has been interpreted as the result of a decreased signal-to-noise ratio in cortical neural networks that process semantic information. Such a decreased signal-to-noise ratio has been related to a decreased dopaminergic modulation (Servan-Schreiber et al. 1990; Cohen and Servan- Schreiber 1992, 1993), which we recently were able to confirm directly in a study on the effects of L-dopa on semantic and indirect semantic priming (Kischka et al 1995).

As dopamine was found to have a focusing effect on the activity in semantic networks, i.e., it increases the signal-to-noise ratio and reduces the spread of activation (measured as reduced indirect semantic priming), we set out to investigate the effect of the hallucinogenic agent psilocybin on this task. Since psilocybin is known to act on the serotonin (5-HT) system and has effects of "broadening" conscious experiences, we hypothesized that it might exert a defocusing effect on semantic networks (i.e., decrease the signal-to-noise ratio), which should lead to an increased indirect semantic priming effect.

To test this hypothesis directly, we conducted a double-blind, placebo-controlled study on the effects of psilocybin on semantic and indirect semantic priming as part of a larger project that was designed to assess the behavioral effects and pharmacokinetic properties of this hallucinogenic agent (the results will be reported elsewhere; cf. Holzmann 1995).

RATIONALE: Binocular rivalry occurs when different images are simultaneously presented to each eye. During continual viewing of this stimulus, the observer will experience repeated switches between visual awareness of the two images. Previous studies have suggested that a slow rate of perceptual switching may be associated with clinical and drug-induced psychosis.

OBJECTIVES: The objective of the study was to explore the proposed relationship between binocular rivalry switch rate and subjective changes in psychological state associated with 5-HT2A receptor activation.

MATERIALS AND METHODS: This study used psilocybin, the hallucinogen found naturally in Psilocybe mushrooms that had previously been found to induce psychosis-like symptoms via the 5-HT2A receptor. The effects of psilocybin (215 microg/kg) were considered alone and after pretreatment with the selective 5-HT2A antagonist ketanserin (50 mg) in ten healthy human subjects.

RESULTS: Psilocybin significantly reduced the rate of binocular rivalry switching and increased the proportion of transitional/mixed percept experience. Pretreatment with ketanserin blocked the majority of psilocybin's "positive" psychosis-like hallucinogenic symptoms. However, ketanserin had no influence on either the psilocybin-induced slowing of binocular rivalry or the drug's "negative-type symptoms" associated with reduced arousal and vigilance.

CONCLUSIONS: Together, these findings link changes in binocular rivalry switching rate to subjective levels of arousal and attention. In addition, it suggests that psilocybin's effect on binocular rivalry is unlikely to be mediated by the 5-HT2A receptor.

Background: Recent findings suggest that the serotonergic system and particularly the 5-HT2A/1A receptors are implicated in visual processing and possibly the pathophysiology of visual disturbances including hallucinations in schizophrenia and Parkinson's disease.

Methods: To investigate the role of 5-HT2A/1A receptors in visual processing the effect of the hallucinogenic 5-HT2A/1A agonist psilocybin (125 and 250 μg/kg vs. placebo) on the spatiotemporal dynamics of modal object completion was assessed in normal volunteers (n = 17) using visual evoked potential recordings in conjunction with topographic-mapping and source analysis. These effects were then considered in relation to the subjective intensity of psilocybin-induced visual hallucinations quantified by psychometric measurement.

Results: Psilocybin dose-dependently decreased the N170 and, in contrast, slightly enhanced the P1 component selectively over occipital electrode sites. The decrease of the N170 was most apparent during the processing of incomplete object figures. Moreover, during the time period of the N170, the overall reduction of the activation in the right extrastriate and posterior parietal areas correlated positively with the intensity of visual hallucinations.

Conclusions: These results suggest a central role of the 5-HT2A/1A-receptors in the modulation of visual processing. Specifically, a reduced N170 component was identified as potentially reflecting a key process of 5-HT2A/1A receptor–mediated visual hallucinations and aberrant modal object completion potential.

The use of hallucinogenic fungi containing psilocybin and or psilocin has, during the past few decades, spread from Central America to the whole western world. Psilocybin (4-phosphoryloxy- N, N-dimethyltryptamine) and psilocin (4-hydroxy-N,N-dimethyltryptamine) were first isolated from Psilocybe mexicana but have later been reported from more than 30 species of the genus and from several species of other genera. In the Scandinavian countries, the most common psilocybin-containing fungus is Psilocybe semilancuta; in all, about ten active species have been reported from Norway and Denmark. In this study, a variety of Finnish fungi were screened for their psilocybin and psilocin content using two methods of hplc.

Background: This research focuses on the events leading to the 1968 U.S. federal prohibition of psilocybin. It is a study of duelling moral entrepreneurs—Timothy Leary and Richard Alpert vs. the Harvard University Administration. The goal is to show how the primary active compound in an ostensibly harmless fungus (the psilocybin mushroom) became controversial in less than a decade.

Methods: We used books, newspapers, magazine articles and previously unpublished materials (including documents from the Harvard Archives) to analyze Leary and Alpert's lives and careers through the early 1970s.

Results: The prohibition of psilocybin in the U.S. was largely a product of Leary and Alpert's involvement in the “Harvard drug scandal” and their transformation from Harvard professors to countercultural icons. They tested the substance on a variety of human subjects and in doing so piqued the interest of Harvard undergraduates while drawing condemnation from other faculty and Harvard administrators. This case is theoretically interesting because unlike most illegal drugs, psilocybin was never linked to a threatening minority group, but to some of the nation's most privileged youth.

Conclusion: The Harvard administrators were not really moral entrepreneurs but Leary and Alpert clearly were. Although they were far from being prohibitionists, they were self-righteous crusaders on different but equally holy missions for the good of young and minority Americans. Ironically, due to their successes the possession of psilocybin was criminalized under United States federal law in 1968 (Pub. L. No. 90-639, Stat. 1361 1968 and Boire, 2002). This case study demonstrates that crusaders can be successful in changing culture even when laws are passed in futile attempts to control their behaviour, just as Leary predicted.

METHODS: Participants were 18 adults (17 hallucinogen-naïve). Five 8-h sessions were conducted individually for each participant at 1-month intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up.

RESULTS: Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects.

The Selva Pascuala mural, a work of post-Paleolithic rock art in Spain, contains fungoid figures herein hypothesized to depict neurotropic fungi, especially Psilocybe hispanica, a species that occurs in a neighboring region. This hypothesis is based on features of these figures related to fungal morphology, along with ethnographic analogy, and shamanistic explanations of rock art. If correct, this interpretation would support inference of prehistoric utilization of this fungus in the region. The mural represents the first direct evidence for possible ritual use of Psilocybe in prehistoric Europe.

In this paper, the world distribution of 216 known species of neurotropic fungi is discussed. The neurotropic fungi considered are divided into the following four groups: 1) species with psilocybin and related indoles, or those likely to contain these substances, 2) species with ibotenic acid, 3) ergot fungi, and 4) species used as sacred fungi for which no reliable chemical studies have been found. In the first group are Psilocybe (116 species), Gymnopilus (14 species), Panaeolus (13 species), Copelandia (12 species), Hypholoma (6 species), Pluteus (6 species), Inocybe (6 species), Conocybe (4 species), Panaeolina (4 species), Gerronema (2 species) and Agrocybe, Galerina and Mycena (each with one species), although in several species of this group, mainly in the Panaeoloideous fungi, there are no known chemical studies. In the second group are Amanita muscaria, A. pantherina and A. regalis; in the third group are Claviceps purpurea and allies: 5 species of Claviceps and 2 of Cordyceps; in the fourth group are bolets (two genera with 8 species), Russula (6 species), and 6 species of gasteromycetes (Lycoperdales y Phallales) in 3 genera. Concerning the distribution of Psilocybe, the majority of the species are found in or near the Austral hemisphere, mainly in the subtropical humid forests. Within these forests reside the most most well documented ethnic groups that use neurotropic fungi, such as the native peoples of Mexico and New Guinea. Mexico has the highest number of neurotropic species of fungi, with 76 species, of which 44 belong to Psilocybe (39 % of the world). More than 450 bibliographic references were considered.

Mycelial cultures of Psilocybe cubensis capable of forming psilocybin and psilocin de novo display a high capacity for hydroxylation of tryptamine derivatives at the 4-position. A specific biotransformation of added synthetic N,N-diethyl-tryptamine was found. Thus high amounts of 4-hydroxy-N,N-diethyltryptamine (up to 3.3%) and a minor quantity of 4-phosphoryloxy-N,N-diethyltryptamine (0.01-0.8%) were isolated from fruiting bodies of Psilocybe cubensis in corresponding experiments. This is the first example of a directed biosynthesis of tryptamine substances by fungi. An effective biotransformation of N-methyltryptamine was also demonstrated with surface cultures of Psilocybe semilanceata. Baeocystin, a possible natural precursor of psilocybin, was detected and quantified in the biomasses. No alkaloids could be found in the culture medium.

Mushrooms containing psilocybin have been used for millennia in primative societies for religious/medical purposes. However, today these fungi are used in Western countries primarily as a form of recreation. Although this use does not seem to be causing significant health problems, more study is needed to evaluate the significance of this phenomenon. Essentially all the ethnobotanical use of Psilocybe cubensis (Earle.) Sing. rests on the fact that it contains the compounds psilocybin and psilocin, both of which are hallucinogenic. The most complete interdisciplinary study of this and other “psilocybin” mushrooms is that of Heim and Wasson (1958). Singer (1958), Singer and Smith (1958), Pollock (1975, 1976), Ott (1976), Lincoff and Mitchel(1977), Ott and Bigwood (1978), Rumack and Salzman (1978), Schultes and Hofmann (1980) and Stamets (1978) have also published works on various aspects of hallucinogenic fungi. Because Psilocybe cubensis grows commonly in the southeastern United States and is easily cultivated (Stamets, 1978), it is probably the most commonly eaten hallucinogenic mushroom in this area today. The unauthorized possession, sale, or use of psilocybin or psilocin is a crime in the United States (Public Law 91-513) although few, if any, people have been convicted of possession of mushrooms. The purpose of this paper is to review the literature of man’s past and present use of psilocybin mushrooms, especially P. cubensis.

The analysis of three bluing species of the genera Psilocybe, Gymnopilus and Conocybe from Germany revealed psilocybin and baeocystin and in some cases psilocin as well. The content of the alkaloids in cultured basidiocarps of Psilocybe semilanceata and Gymnopilus purpuratus was in the same order of magnitude as that found in naturally grown mushrooms. For the first time, the psilocybin containing non-bluing mycelium of Conocybe cyanopus could be cultivated.

Aeruginascin is a natural product from the hallucinogenic mushroom Inocybe aeruginascens. This compound was isolated and identified as 4-phosphoryloxy-N,N,N-trimethyltryptamine. Aeruginascin is the quaternary trimethylammonium analog of the hallucinogenic compound psilocybin. Synthetic aeruginascin was identical in all aspects to the isolated sample. Additionally, the mushroom alkaloids norbaeocystin and baeocystin were synthesized and a new synthetic approach to 4‑hydroxy-tryptamines was investigated.

After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.

« Viimeksi muokattu: Toukokuu 31, 2016, 01:16 kirjoittanut Arvalis »

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

The genus Psilocybe contains iconic species of fungi renowned for their hallucinogenic properties. Recently, Psilocybe also included non-hallucinogenic species that have since been shifted to the genus Deconica. Here, we reconstruct a multigene phylogeny for Psilocybe, Deconica, and other exemplars of the families Hymenogastraceae and Strophariaceae sensu stricto (s. str.), using three nuclear markers (nLSU-rRNA, 5.8S rRNA, and rpb1). Our results confirm the monophyly of Deconica within Strophariaceae s. str., as well as numerous robust infrageneric relationships. Psilocybe is also recovered as a monophyletic group in the Hymenogastraceae, in which two principal lineages are recognized, including several nested subgroups. Most sections of Psilocybe following classifications based on morphological features are not supported in these analyses. Ancestral character state reconstruction analyses suggest that basidiospore shape in frontal view and spore wall thickness, commonly used to characterize sections in Deconica and Psilocybe, are homoplastic. Chrysocystidia, sterile cells located in the hymenium, evolved on at least two occasions in the Strophariaceae s. str., including in a novel lineage of Deconica.

BACKGROUND: Serotonin (5-HT) 1A and 2A receptors have been associated with dysfunctional emotional processing biases in mood disorders. These receptors further predominantly mediate the subjective and behavioral effects of psilocybin and might be important for its recently suggested antidepressive effects. However, the effect of psilocybin on emotional processing biases and the specific contribution of 5-HT2A receptors across different emotional domains is unknown.

CONCLUSIONS: This study shows that psilocybin shifts the emotional bias across various psychological domains and that activation of 5-HT2A receptors is central in mood regulation and emotional face recognition in healthy subjects. These findings may not only have implications for the pathophysiology of dysfunctional emotional biases but may also provide a framework to delineate the mechanisms underlying psylocybin's putative antidepressant effects.

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin—prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells.

« Viimeksi muokattu: Helmikuu 19, 2014, 18:52 kirjoittanut Arvalis »

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Formation of basidiocarp initials in Psilocybe cubensis occurred only when cultures were illuminated. Short durations of light (0.0025 sec of xenon-arc flash) were sufficient for initiation. Light-induced initiation was saturated at a dose of 3450 erg/cm^2 at 460 nm. UV and blue wavelengths of 370, 440 and 460 nm were the most effective. Green and red wavelengths greater than 510 nm were ineffective.

A new method has been developed for the rapid analysis of psilocybin and/or psilocin in fungus material using ion mobility spectrometry. Quantitative analysis was performed by gas chromatography-mass spectrometry after a simple one-step extraction involving homogenization of the dried fruit bodies of fungi in chloroform and derivatization with MSTFA. The proposed methods resulted in rapid procedures useful in analyzing psychotropic fungi for psilocybin and psilocin.

Lainaus

Data about the content of psilocybin and psilocin in mushrooms of Psilocybe cubensis were first reported by Repke et al. and later by Borner and Brenneisen and Gartz . According to these authors the amount of psilocybin varies from 0.17 to 1.07%. The content of psilocin is reported within the range of 0.11–0.42% per dry mass. Our investigations of fruit bodies of Psilocybe subcubensis show a similar content [0.83%] of the major component psilocybin, whereas the psilocin level seems to be much lower [0.025%].

Differences in the psilocybin and psilocin content of fruit bodies of Psilocybe species are to be expected since the amount of active components present in the corresponding mushrooms undoubtedly depends on factors such as species, time of collection, climatic conditions, preservation of the material as well as the availability of soluble nitrogen and phosphorus in the soil.

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects. However, it is also a very popular and frequently abused natural hallucinogen. This review summarizes all the past and recent knowledge on psilocybin. It briefly deals with its history, discusses the pharmacokinetics and pharmacodynamics, and compares its action in humans and animals. It attempts to describe the mechanism of psychedelic effects and objectify its action using modern imaging and psychometric methods. Finally, it describes its therapeutic and abuse potential.

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Background: The amygdala is a key structure in serotonergic emotion-processing circuits. In healthy volunteers, acute administration of the serotonin 1A/2A/2C receptor agonist psilocybin reduces neural responses to negative stimuli and induces mood changes towards positive states. However, it is little-known whether psilocybin reduces amygdala reactivity to negative stimuli and whether any change in amygdala reactivity is related to mood change.

Methods: This study assessed the effects of acute administration of the hallucinogen psilocybin (0.16 mg/kg) vs. placebo on amygdala reactivity to negative stimuli in 25 healthy volunteers using blood oxygenation level-dependent functional magnetic resonance imaging. Mood changes were assessed using the Positive and Negative Affect Schedule and the state portion of the State-Trait Anxiety Inventory. A double-blind, randomized, cross-over design was used with volunteers counterbalanced to receive psilocybin and placebo in two separate sessions at least 14 days apart.

Results: Amygdala reactivity to negative and neutral stimuli was lower after psilocybin administration than after placebo administration. The psilocybin-induced attenuation of right amygdala reactivity in response to negative stimuli was related to the psilocybin-induced increase in positive mood state.

Conclusions: These results demonstrate that acute treatment with psilocybin decreased amygdala reactivity during emotion processing, and that this was associated with an increase of positive mood in healthy volunteers. These findings may be relevant to the normalization of amygdala hyperactivity and negative mood states in patients with major depression.

Rationale: Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT2A) receptors.

Objectives: This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects.

Results: Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT2A, serotonin 1A (5-HT1A), and 5-HT2A β-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT2A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT1A agonists. Most tryptamines recruited β-arrestin through 5-HT2A activation.

Conclusions: All psychoactive tryptamines are 5-HT2A agonists, but 5-HT transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds. The in vitro transporter data confirm structure-activity trends for releasers and uptake inhibitors whereby releasers tend to be structurally smaller compounds. Interestingly, two tertiary amines were found to be selective substrates at SERT, which dispels the notion that 5-HT-releasing activity is limited only to primary or secondary amines.

Psilocin was found to have reasonable uptake inhibitory properties at the SERT [serotonin transporter], with an IC50 value of 662 nM. The transposition of the hydroxyl group from the 5-position (16) to the 4-position (24) changed the activity from a SERT mediated releaser to a SERT uptake inhibitor, meaning the 5-substituted compound was a substrate, but the 4-substituted analog was not.

« Viimeksi muokattu: Tammikuu 10, 2015, 07:48 kirjoittanut Arvalis »

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of “primary states” is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. Indeed, since there is a greater repertoire of connectivity motifs in the psychedelic state than in normal waking consciousness, this implies that primary states may exhibit “criticality,” i.e., the property of being poised at a “critical” point in a transition zone between order and disorder where certain phenomena such as power-law scaling appear. Moreover, if primary states are critical, then this suggests that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes normal waking consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is [also] proposed that entry into primary states depends on a collapse of the normally highly organized activity within the default-mode network (DMN) and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled). These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as rapid eye movement (REM) sleep and early psychosis and comparing these with non-primary states such as normal waking consciousness and the anaesthetized state.

« Viimeksi muokattu: Tammikuu 10, 2015, 07:47 kirjoittanut Arvalis »

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

Lainaus

The data reported demonstrate that the administration of PSOP produced a biphasic response in hippocampal neurogenesis; a low dose (0.1 mg/kg) resulted in a trend toward increased neurogenesis, whereas the high dose of PSOP significantly decreased the formation of new neurons measured 2 weeks after drug exposure. In addition, all doses of the potent 5-HT2A receptor agonist 25I-NBMeO and the 5-HT2A/C receptor antagonist ketanserin decreased hippocampal neurogenesis.

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

The study of rapid changes in brain dynamics and functional connectivity (FC) is of increasing interest in neuroimaging. Brain states departing from normal waking consciousness are expected to be accompanied by alterations in the aforementioned dynamics. In particular, the psychedelic experience produced by psilocybin (a substance found in `magic mushrooms`) is characterized by unconstrained cognition and profound alterations in the perception of time, space and selfhood. Considering the spontaneous and subjective manifestation of these effects, we hypothesize that neural correlates of the psychedelic experience can be found in the dynamics and variability of spontaneous brain activity fluctuations and connectivity, measurable with functional Magnetic Resonance Imaging (fMRI). Fifteen healthy subjects were scanned before, during and after intravenous infusion of psilocybin and an inert placebo. Blood-Oxygen Level Dependent (BOLD) temporal variability was assessed computing the variance and total spectral power, resulting in increased signal variability bilaterally in the hippocampi and anterior cingulate cortex. Changes in BOLD signal spectral behavior (including spectral scaling exponents) affected exclusively higher brain systems such as the default mode, executive control and dorsal attention networks. A novel framework enabled us to track different connectivity states explored by the brain during rest. This approach revealed a wider repertoire of connectivity states post-psilocybin than during control conditions. Together, the present results provide a comprehensive account of the effects of psilocybin on dynamical behaviour in the human brain at a macroscopic level and may have implications for our understanding of the unconstrained, hyper-associative quality of consciousness in the psychedelic state.

Lainaus

[...] a greater diversity of connectivity motifs was observed after psilocybin, reflecting increased entropy in this system's dynamical behavior. Overall these quantities demonstrate an increase in the dynamical repertoire (i.e., new states) in the brain under psilocybin as well as an increase in the rate at which the repertoire is examined.

Lainaus

[...] it seems that a primary action of psilocybin, and likely other psychedelics, is to cause a generalized desynchrony and loss of oscillatory power in higher level cortical regions - likely via serotonin 2A receptor mediated excitation of deep-layer pyramidal neurons in these regions. However, the high amplitude activity detected in the hippocampi and anterior cingulate cortex suggests that this desynchronizing eect does not generalize to these deeper structures.

« Viimeksi muokattu: Syyskuu 14, 2015, 23:15 kirjoittanut Arvalis »

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.

« Viimeksi muokattu: Syyskuu 14, 2015, 23:15 kirjoittanut Arvalis »

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Mushroom-forming fungi produce a wide array of toxic alkaloids. However, evolutionary analyses aimed at exploring the evolution of muscarine, a toxin that stimulates the parasympathetic nervous system, and psilocybin, a hallucinogen, have never been performed. The known taxonomic distribution of muscarine within the Inocybaceae is limited, based only on assays of species from temperate regions of the northern hemisphere. Here, we present a review of muscarine and psilocybin assays performed on species of Inocybaceae during the last fifty years. To supplement these results, we used liquid chromatography–tandem mass spectrometry (LC–MS/MS) to determine whether muscarine was present in 30 new samples of Inocybaceae, the majority of which have not been previously assayed or that originated from either the tropics or temperate regions of the southern hemisphere. Our main objective is to test the hypothesis that the presence of muscarine is a shared ancestral feature of the Inocybaceae. In addition, we also test whether species of Inocyabceae that produce psilocybin are monophyletic. Our findings suggest otherwise. Muscarine has evolved independently on several occasions, together with several losses. We also detect at least two independent transitions of muscarine-free lineages to psilocybin-producing states. Although not ancestral for the family as a whole, muscarine is a shared derived trait for an inclusive clade containing three of the seven major lineages of Inocybaceae (the Inocybe, Nothocybe, and Pseudosperma clades), the common ancestor of which may have evolved ca. 60 million years ago. Thus, muscarine represents a conserved trait followed by several recent losses. Transitions to psilocybin from muscarine-producing ancestors occurred more recently between 10–20 million years ago after muscarine loss in two separate lineages. Statistical analyses firmly reject a single origin of muscarine-producing taxa.

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Networks, as efficient representations of complex systems, have appealed to scientists for a long time and now permeate many areas of science, including neuroimaging (Bullmore and Sporns 2009). Traditionally, the structure of complex networks has been studied through their statistical properties and metrics concerned with node and link properties, e.g. degree-distribution, node centrality and modularity. Here, we study the characteristics of functional brain networks at the mesoscopic level from a novel perspective that highlights the role of inhomogeneities in the fabric of functional connections. This can be done by focusing on the features of a set of topological objects—homological cycles—associated with the weighted functional network. We leverage the detected topological information to define the homological scaffolds, a new set of objects designed to represent compactly the homological features of the correlation network and simultaneously make their homological properties amenable to networks theoretical methods. As a proof of principle, we apply these tools to compare resting-state functional brain activity in 15 healthy volunteers after intravenous infusion of placebo and psilocybin—the main psychoactive component of magic mushrooms. The results show that the homological structure of the brain's functional patterns undergoes a dramatic change post-psilocybin, characterized by the appearance of many transient structures of low stability and of a small number of persistent ones that are not observed in the case of placebo.

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson

Five Psilocybe species with unresolved systematic position (P. atrobrunnea, P. laetissima, P. medullosa, P. pelliculosa, and P. silvatica) were investigated using four molecular markers (EF1-α, ITS, LSU, and IGS). Phylogenetic analysis revealed that with the exception of P. laetissima, which is now rightfully classiﬁed in the genus Leratiomyces, all investigated species belong to Psilocybe sect. Psilocybe. For the ﬁrst time, psychotropic compounds psilocin and psilocybin were detected in P. medullosa using gas chromatography-mass spectrometry. On the contrary, neither psilocin, nor psilocybin was detected in P. atrobrunnea and negative results were also obtained from mycelia grown in vitro on tryptamine/tryptophan-amended media. These results strongly suggest that biosynthesis of these alkaloids was lost in P. atrobrunnea. With the exception of minor differences detected in EF1-α marker, all sequences of American and European collections of P. atrobrunnea were identical. On the other hand, a thorough nomenclatural study revealed that the name P. atrobrunnea must be considered dubious; the oldest available candidate name, P. fuscofulva, was therefore adopted. The molecular data suggests that morphologically identical American P. silvatica and European P. medullosa likely represent distinct species; epitypes of both taxa were therefore designated.

Kirjattu

"Beyond a certain point, the whole universe becomes a continuous process of initiation."-- Robert Anton Wilson